The exploration of large-scale active site motions, and their affect on ligand discovery and optimization, is currently one of the most under-investigated areas in structure-based drug design. The proposed "SMD- relaxed complex" method addresses the challenge of increasing the receptor conformational space in a computationally efficient manner. Steered molecular dynamics simulations will be employed to remove a bound ligand from the receptor's active site, thereby accelerating the sampling of the receptor's conformational space. For receptors with deeply buried ligands or flexible loops, this technique could add significant insight into the prediction and evaluation of large domain motions and the effects of active site flexibility on inhibitor binding. The resulting receptor conformations will be ordered with the QR factorization algorithm, and the non-redundant, representative set of structures will be used to develop novel pharmacophore models and as input to the relaxed complex drug design protocol. The success of this new approach will be demonstrated on an essential RNA editing enzyme found in the trypanosomatid pathogens, which are responsible for several devastating tropical diseases. [unreadable] [unreadable] [unreadable]